During murine development, definitive hematopoietic stem cells (HSCs) originate in the dorsal aorta within the aorta-gonad-mesonephros (AGM) region (North, T. E. et al., Immunity 16:661-672 (2002); de Bruijn, M. F. et al., EMBO J 192:465-2474 (2000); Medvinsky, A. et al., Cell 86:897-906 (1996)). In vertebrates, including zebra fish, murine, and possibly human, HSCs are believed to emerge from the layer of hemogenic vascular cells lining the dorsal aorta floor and umbilical arteries (Zovein, A. C. et al., Cell Stem Cell 3:625-636 (2008); Boisset, J. C. et al., Nature 464:116-120 (2010); Bertrand, J. Y. et al., Nature 464:108-111 (2010); Kissa, K. et al., Nature 464:112-115 (2010)). Close association of developing endothelial cells (ECs) and HSC precursor cells in the embryo has led to an EC-hematopoietic transition theory of hematopoiesis (Zovein, A. C. et al., Cell Stem Cell 3:625-636 (2008)). Although it is known that HSCs and definitive erythroid/myeloid progenitors (EMPs) arise from multiple sites containing hemogenic ECs, it has been difficult to characterize the molecular programs driving the spontaneous ontogenetic transition of primitive hemogenic ECs to hematopoietic progenitors (Chen, M. J. et al., Nature 457:887-891 (2009); North, T. E. et al., Cell 137:736-748 (2009)). However, it is commonly accepted that de-novo hematopoiesis does not occur post-natally.
It has been shown that during development of mammals, transitioning ECs/HECs are CD144+CD45+, but that expression of CD144 (also called VE-cadherin) was downregulated soon after the emergence of HSCs from embryonic HECs (North, T. E. et al., Immunity 16:661-672 (2002)). Kim et al. (Blood 106:903-905 (2005)) further identified CD144 expression as present on murine fetal liver HSCs at embryonic day E13.5, declining in expression at embryonic day E16.5, and absent in HSCs in liver and bone marrow by adulthood. CD144+CD45+ transitioning ECs/HECs are thus only known to be present in the embryo and not shown to be present after birth. Whether hemogenic endothelial cells exist anywhere within the organism after birth and whether post-natal endothelium is capable of giving rise to new HSCs and/or multi-potent hematopoietic progenitors are unknown.
Identification of cells with hemogenic potential in post-natal mammals would open up new possibilities for regeneration of the hematopoietic system.